U.S. patent number 8,968,773 [Application Number 12/300,875] was granted by the patent office on 2015-03-03 for silicone film former for delivery of actives.
This patent grant is currently assigned to Dow Corning Corporation. The grantee listed for this patent is Virginie Caprasse, David Clayton Gantner, Eric Jude Joffre, Csilla Kollar, Victor A. Raul, Xavier Thomas. Invention is credited to Virginie Caprasse, David Clayton Gantner, Eric Jude Joffre, Csilla Kollar, Victor A. Raul, Xavier Thomas.
United States Patent |
8,968,773 |
Thomas , et al. |
March 3, 2015 |
Silicone film former for delivery of actives
Abstract
The invention provides: a cross-linkable therapeutic composition
comprising a) a saccharide-siloxane copolymer; b) a crosslinking
agent; c) one or more active/inactive ingredients; and d)
optionally, a solvent, or solvent mixture, wherein the
saccharide-siloxane copolymer has the following formula:
R.sub.2aR.sub.1(3-a)SiO--[(SiR.sub.2R.sub.1O)m-(SiR.sub.12O)n]y-SiR.sub.1-
(3-a)R.sub.2a that is further formulaically defined and wherein the
saccharide-siloxane copolymer is a reaction product of a
functionalized organosiloxane polymer and at least one
hydroxy-functional saccharide such that the organosiloxane
component is covalently linked via a linking group to the
saccharide component; films; and methods related thereto. The
composition has therapeutic properties. The invention also provides
articles of manufacture including topical and transdermal agent
delivery patches comprising the novel film-forming composition
and/or films.
Inventors: |
Thomas; Xavier (Famars,
FR), Caprasse; Virginie (Oreye, BE),
Joffre; Eric Jude (Midland, MI), Kollar; Csilla
(Midland, MI), Gantner; David Clayton (Midland, MI),
Raul; Victor A. (Midland, MI) |
Applicant: |
Name |
City |
State |
Country |
Type |
Thomas; Xavier
Caprasse; Virginie
Joffre; Eric Jude
Kollar; Csilla
Gantner; David Clayton
Raul; Victor A. |
Famars
Oreye
Midland
Midland
Midland
Midland |
N/A
N/A
MI
MI
MI
MI |
FR
BE
US
US
US
US |
|
|
Assignee: |
Dow Corning Corporation
(Midland, MI)
|
Family
ID: |
38779183 |
Appl.
No.: |
12/300,875 |
Filed: |
May 23, 2007 |
PCT
Filed: |
May 23, 2007 |
PCT No.: |
PCT/US2007/012260 |
371(c)(1),(2),(4) Date: |
February 18, 2009 |
PCT
Pub. No.: |
WO2007/139812 |
PCT
Pub. Date: |
December 06, 2007 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20090258058 A1 |
Oct 15, 2009 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60802708 |
May 23, 2006 |
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Current U.S.
Class: |
424/449; 424/404;
525/474; 524/588; 424/488 |
Current CPC
Class: |
A61K
9/7069 (20130101); C08G 77/14 (20130101); C08G
77/388 (20130101); A61K 9/7015 (20130101); C08L
83/06 (20130101); A61P 31/00 (20180101); C08L
83/06 (20130101); C08L 83/00 (20130101); C08L
83/08 (20130101); C08K 5/55 (20130101) |
Current International
Class: |
A61K
9/70 (20060101); A61K 9/14 (20060101); A01N
25/34 (20060101); C08L 83/04 (20060101) |
References Cited
[Referenced By]
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applicant .
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pages. cited by applicant .
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.
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of guar by borate; dated Mar. 21, 2012; 1 page. cited by applicant
.
Extended European Search Report PCT/US2007-012260; dated Mar. 21,
2012; 7 pages. cited by applicant.
|
Primary Examiner: Palenik; Jeffrey T
Attorney, Agent or Firm: Nixon Peabody LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a U.S. national phase of International
Application No. PCT/US2007/012260, filed May 23, 2007, which claims
the benefit of priority of U.S. Provisional Application No.
60/802,708, filed on May 23, 2006, both of which are incorporated
by reference in their entireties.
Claims
The invention claimed is:
1. A cross-linkable therapeutic film composition comprising: a) a
saccharide-siloxane copolymer; b) a crosslinking agent; c) about
0.1 to about 70 wt % of one or more active/inactive ingredients;
and d) at least one of a solvent and solvent mixture, wherein the
saccharide-siloxane copolymer has the following formula:
R.sup.2.sub.aR.sup.1.sub.(3-a)SiO--[(SiR.sup.2R.sup.1O).sub.m--(SiR.sup.1-
.sub.2O).sub.n].sub.y--SiR.sup.1.sub.(3-a)R.sup.2.sub.a wherein
R.sup.1 can be the same or different and comprises hydrogen,
C.sub.1-C.sub.12 alkyl, an organic radical, or R.sup.3--Q, Q
comprises an epoxy, cycloepoxy, primary or secondary amino,
ethylenediamine, carboxy, halogen, vinyl, allyl, anhydride, or
mercapto functionality, m and n are integers between 0 and 10,000
and may be the same or different, each a is independently 0, 1, 2,
or 3, y is an integer such that the copolymer has a molecular
weight less than 1 million,
R.sup.1.sub.(3-a)SiO--[(SiR.sup.2R.sup.1O).sub.m--(SiR.sup.1.sub.2O).sub.-
n].sub.y--SiR.sup.1.sub.(3-a) is an organosiloxane polymer
component, R.sub.2 has the formula
Z--(G.sup.1).sub.b-(G.sup.2).sub.c, and there is at least one
R.sup.2 per copolymer, wherein G.sup.1 is a saccharide component
comprising 5 to 12 carbons, b+c is 1-10, b or c can be 0, either b
or c must be 1, G.sup.2 is a saccharide component comprising 5 to
12 carbons additionally substituted with organic or organosilicon
radicals, Z is a linking group between the organosiloxane polymer
component and the saccharide component and is independently
selected from the group consisting of:
--R.sup.3--NHC(O)--R.sup.4--; --R.sup.3--NHC(O)O--R.sup.4--;
--R.sup.3--NH--C(O)--NH--R.sup.4--; --R.sup.3--C(O)--O--R.sup.4--;
--R.sup.3--O--R.sup.4--; --R.sup.3--S--R.sup.4--;
--R.sup.3--CH(OH)--CH.sub.2--O--R.sup.4 --;
--R.sup.3--CH(OH)--CH.sub.2--NH--R.sup.4--; and
--R.sup.3--N(R.sup.1)--R.sup.4 , and R.sup.3 and R.sup.4 are
divalent spacer groups comprising
(R.sup.5).sub.r(R.sup.6).sub.s(R.sup.7).sub.t, where at least one
of r, s and t must be 1, R.sup.5 and R.sup.7 are either
C.sub.1-C.sub.12 alkylene or ((C.sub.1-C.sub.12)O).sub.p where p is
any integer 1-50 and each (C.sub.1-C.sub.12)O may be the same or
different, and R.sup.6 is --N(R.sup.8)--, where R.sup.8 is H or
C.sub.1-C.sub.12 alkyl or is Z--X, wherein Z is previously defined
or R.sup.3, wherein the film composition has therapeutic
properties, the film composition having a thickness of up to 500
microns.
2. The film composition of claim 1 wherein the saccharide siloxane
copolymer comprises a hydroxyl functionality of at least three.
3. The film composition of claim 1 wherein the at least one
Polyhydroxyl-functional saccharide comprises an aldonic acid or an
oligoaldonic acid.
4. The film composition of claim 3 wherein the aldonic acid or the
oligoaldonic acid comprises a lactone.
5. The film composition of claim 4 wherein the lactone comprises
gluconolactone or lactobionolactone.
6. The film composition of claim 1 wherein the linking group
comprises an amide, an amino, a urethane, a urea, an ester, an
ether, a thioether, or an acetal linking group.
7. The film composition of claim 1, wherein the at least one
Polyhydroxyl-functional saccharide comprises gluconolactone and the
functionalized organosiloxane polymer comprises a
polydimethylsiloxane having pendant minoethylaminoisobutyl
groups.
8. The film composition of claim 1, further comprising one or more
additional saccharide-siloxane copolymers and suitable cross
linkers to form a blended film-forming composition.
9. The film composition of claim 1 further delivered onto a
biological substrate and forming a cohesive and substantive
film.
10. The film composition of claim 9, wherein the one or more active
or/and inactive ingredients is selected from the following: a
catalyst; a filler; a pigment; a UV stabilizer; a fragrance; an
essential oil; a thermal stabilizer; a rheology modifier; a
thickener; an adhesion promoter; a biocide; an antifungal; an
antibiotic; a preservative; an enzyme; a peptide; a pressure
sensitive adhesive; a surface-active agent; a pharmaceutical
active; a cosmetic ingredient; a resin; and an aqueous
ingredient.
11. The film composition of claim 10 wherein the biological
substrate comprises human skin or nail.
12. The film composition of claim 11 wherein the is incorporated
into a wound dressing, a bandage, a transdermal drug delivery
patch, a topical drug delivery formulation, a cosmetic composition
or a fragrance delivery patch.
13. The film composition of claim 1, wherein the active ingredient
comprises a medicament or pharmaceutical agent and the composition
is incorporated into a transdermal drug delivery patch.
14. The film composition of claim 1, wherein the active ingredient
comprises at least one biocide.
15. A method for delivering at least one active agent topically to,
or transdermally through a biological substrate, the method
comprising: wet application of the cross-linkable therapeutic film
composition according to claim 1 to a biological substrate, and
curing the composition to form a film directly on the biological
substrate.
Description
FIELD OF THE INVENTION
The present invention relates to the use of saccharide siloxane
copolymer compositions that rapidly cure for forming films and
delivering actives in personal and healthcare applications.
BACKGROUND OF THE INVENTION
The compositions comprise a single or a blend of saccharide
siloxane copolymers that is cross-linked in the presence of
reactive cross-linking agents. A preferred saccharide siloxane
composition for use in the present invention is a
saccharide-derived polyhydroxyl-functional moiety covalently linked
to an organosilicon backbone. The cross-linking is achieved by
reacting suitable reactive cross-linkers to the copolymers via the
polyhydroxy-functionality of the saccharide components.
These film-forming compositions can be used to form a cohesive and
substantive films on human or animal biological tissues. The
resulting film is designed to deliver actives to the adhering
substrate and to the underlying layers. It can also be a protective
and barrier film for the covered area, and be used to modify the
hydration of the underlying tissues. It can also provide an
aesthetic and cosmetic aspect to the covered surface. Thus, it has
utility in topical administration, wound care and skin care
applications. The invention further relates to the film forming
compositions, cured films, and articles of manufacture comprised
thereof.
Many formulations for forming films are known in the cosmetic,
medical and pharmaceutical art. These include, for example,
ointments, salves, creams, lotions, gels, elastomers and the like.
Some of these formulations use silicone-based materials as key
components. Silicone based materials are desirable in these
formulations since they are generally inert to the body. These
products are designed to provide a variety of benefits, for
example, moisturize dry skin, mask surface imperfections, allow
effective delivery of actives while being cosmetically acceptable
during and after application onto various skin areas of the
body.
Well-known formulations are based on blends of silicone fluids and
are broadly used in cosmetic skin care. They combine various
viscosities of silicone fluids from volatiles to gum type materials
as described in U.S. Pat. No. 6,325,990. Other formulations contain
cross-linked organosiloxanes swollen in low molecular weight
silicone fluids, and are referred to as elastomer blends as
described in U.S. Pat. Nos. 5,654,362 and 6,221,979, and in
European Publication Nos: EP848029, EP869142, EP934959, EP1020494,
and EP1057872. These compositions show interesting film forming
property by spreading easily to various surfaces but their
substantivity is low due to an intrinsic cohesion weakness.
Similar compositions, as described for example in WO 97/17057, WO
97/17058, and WO 97/17059, are obtained by blending silicate
resins, such as those described in U.S. Pat. Nos. 3,936,582,
2,676,182, 2,857,356 and 2,676,182, with silicone fluids. These
compositions show interesting film forming property by spreading
easily to various surfaces but their substantivity is limited due
to lack of condensation between the resin and the polymeric
fluid.
The silicate resin and the silicone fluid can be condensed together
according to Canadian Application No. 711,756. The resulting
material most likely has adhesive pressure sensitive properties as
described in Handbook of Pressure Sensitive Adhesive Technology,
3.sup.rd edition by Donatas Satas, Satas & Associates, Warwick,
R.I. 1989 (ISBN #0963799339), and EP 0180377. These compositions
show interesting film forming properties as well as high
substantivity and basically demonstrate no tack (essentially,
resistance to separation, or, generally, "stickiness") property at
high resin content (defined as greater than about 65 weight
percent); however because of their intrinsic visco-elastic property
they remain sensitive to plasticizing effects and may become
tackier by absorbing plasticizing species.
Another example of silicon-based materials in known film forming
formulations is provided in European Publication 465,744. This
publication teaches the use of a multi-part formulation including
an active agent, a Si--H containing polymer, a polymer having
unsaturated groups bound to silicon, a catalyst and a hydrophilic
component. The formulation is mixed and applied to the body where
it cures and forms a controlled release gel. This cross-linkable
and elastomeric composition allows for significant reduction of
sensitivity to plasticizing effect. The prior art methods such as
those described in EP 465,744, however, have several disadvantages.
For instance, in such methods the person utilizing the formulation
must be skilled so as to ensure adequate mixing of the appropriate
amounts of component materials in the formulation. Special care
must be exercised to apply the correct amount of the mixed
formulation to the desired site before it gels. Similarly, such a
method can be an inconvenient and messy for the end user. Similar
systems are described in the following publications U.S. Pat. No.
6,471,985, EP 0 506 241, EP 0 865 787, and WO 2004/108175.
Another patent document, WO 90/03809, teaches a coating material
for forming bandages comprising a siloxane-containing bandage
material diluted in a volatile polydimethylsiloxane. These coatings
are distinguishable from the films described and claimed herein.
Similar systems are described in the following publications EP
0438496, EP0572416, however these patents describe polymers with
acrylate backbones and pendant siloxane functionality.
GB 2407496 and WO 01/96450 teach a method for forming a film on a
biological surface. The method comprises mixing an alkylene
trialkoxysilyl-terminated polysiloxane; an alkoxysilane; a titanate
catalyst; a filler; and a volatile diluent to form a formulation.
The formulation is then applied onto a biological surface where it
cures in situ on the surface to form a film. This film-former
suffers from the characteristic that it cures upon contact with
moisture, making it very sensitive to humidity and impacting its
stability if it is not properly packaged.
Other known options include solutions of nitrocellulose-silicone
blends or silicone-polyamide compositions. While the methods
described above may allow for delivering certain important
properties, none of them have demonstrated the capability to
deliver all important properties in a single embodiment.
Organosiloxane-based elastomers formed from crosslinking
organosiloxane polymers are well known in the art and such
materials have wide-ranging utility as coatings which confer
desirable surface properties to the coated substrate. Such
properties include, for example, enhanced resistance to wear,
thermal stability, hydrophobicity and resistance to water, adhesion
control and release, frictional control including anti-slip
capability, and the like. Various fillers and other additives may
be included within the elastomeric matrix to provide coatings with
even more varied performance benefits. The mechanical, chemical and
ionic characteristics of the crosslinked network matrix influences
both the nature and amount of additives that may suitably be
included.
Compositions and cured coating compositions comprising crosslinked
carbohydrates are known in the art. However, the present inventors
are unaware of film-forming compositions comprising
saccharide-siloxane copolymers crosslinked via the polyhydroxyl
functionality of the saccharide. The networked matrix and cured
films formed from these unique crosslinkable compositions provide a
blended property profile comprising attributes of both silicone and
carbohydrate-based matrices which may support, retain and/or
controllably release a variety of additives. Crosslinking via the
saccharide component of the copolymer yields elastomers possessing
a property profile making them desirable for particular
applications.
There is a need in the art for film-forming compositions capable of
delivering actives to and through biological substrates. The cured
films comprised therefrom, which reflect the benefits and
characteristics known to be imparted by films that comprise both
silicone and carbohydrate components.
SUMMARY OF THE INVENTION
According to one embodiment of the invention, a cross-linkable
therapeutic composition is disclosed. The composition includes a
saccharide-siloxane copolymer, a crosslinking agent, one or more
active/inactive ingredients, and at least one of a solvent and
solvent mixture. The saccharide-siloxane copolymer has the
following formula:
R.sup.2.sub.aR.sup.1.sub.(3-a)SiO--[(SiR.sup.2R.sup.1O).sub.m--(SiR.sup.1-
.sub.2O).sub.n].sub.y--SiR.sup.1.sub.(3-a)R.sup.2.sub.a. R.sup.l
can be the same or different and comprises hydrogen,
C.sub.1-C.sub.12 alkyl, an organic radical, or R.sup.3-Q. Q
comprises an epoxy, cycloepoxy, primary or secondary amino,
ethylenediamine, carboxy, halogen, vinyl, allyl, anhydride, or
mercapto functionality. m and n are integers between 0 and 10,000
and may be the same or different. Each a is independently 0, 1, 2,
or 3. y is an integer such that the copolymer has a molecular
weight less than 1 million.
R.sup.1.sub.(3-a)SiO--[(SiR.sup.2R.sup.1O).sub.m--(SiR.sup.1.sub.2O).sub.-
n].sub.y--SiR.sup.1.sub.(3-a) is an organosiloxane polymer
component. R.sub.2 has the formula
Z-(G.sup.1).sub.b-(G.sup.2).sub.c, and there is at least one
R.sup.2 per copolymer. G.sup.1 is a saccharide component comprising
5 to 12 carbons, b+c is 1-10, b or c can be 0, either b or c must
be 1, G.sup.2 is a saccharide component comprising 5 to 12 carbons
additionally substituted with organic or organosilicon radicals,
and Z is a linking group between the organosiloxane polymer
component and the saccharide component and is independently
selected from the group consisting of:
--R.sup.3--NHC(O)--R.sup.4--, --R.sup.3--NHC(O)O--R.sup.4--,
--R.sup.3--NH--C(O)--NH--R.sup.4--,
--R.sup.3----C(O)--O--R.sup.4--,
--R.sup.3--S--R.sup.4--,--R.sup.3--CH(OH)--CH.sub.2--O--R.sup.4--,--R.sup-
.3--CH(OH)--CH.sub.2--NH--R.sup.4--, and
--R.sup.3--N(R.sub.1)--R.sup.4. R.sup.3 and R.sup.4 are divalent
spacer groups comprising
(R.sup.5).sub.r(R.sup.6).sub.s(R.sup.7).sub.t, where at least one
of r, s and t must be 1, R.sup.5 and R.sup.7 are either
C.sub.1-C.sub.12 alkylene or ((C.sub.1-C.sub.12)O).sub.p where p is
any integer 1-50 and each (C.sub.1-C.sub.12)O may be the same or
different, and R.sup.6 is --N(R.sup.8)--, where R.sup.8 is H or
C.sub.1-C.sub.12 alkyl, or is Z--X, wherein Z is previously defined
or R.sup.3. The composition has therapeutic properties.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1. Illustrates drug release embodiments according to the
present invention.
FIG. 1A. sets forth data relating to cumulative release of the drug
agent Niacinamide from inventive films.
FIG. 1B. sets forth data relating to cumulative release of the drug
agent Ketoconazole from inventive films. Determination of active
agent release was conducted using Franz static diffusion cells
having defined receiving volumes.
DETAILED DESCRIPTION
Accordingly, the present invention is based on the novel discovery
of a film-forming composition and methods of making a film that
avoids many of the prior art problems discussed above, and the
films are therefore particularly useful in personal and healthcare
applications. The presently inventive film-forming composition
permits the combination into one technology of a substantive film
former delivered in a pleasant carrier which is able to stabilize
and release actives.
The present invention utilizes saccharide-derived polyhydroxyl
siloxanes to form crosslinked networks via linking between the
saccharides in the presence of a suitably reactive crosslinking
agent, for example, borate or titanate esters and acids. The
crosslinking occurring between the hydroxyl functionalities of the
saccharide backbone of the copolymers is unique and forms a
three-dimensional network having a unique matrix. Consequently, the
films formed therefrom possess unique property profiles. While not
being bound by theory, the resulting films combine the properties
of siloxanes like, softness, vapor permeability, hydrophobicity,
good aesthetic feel, adhesive release, & flexibility with the
attributes of saccharides like substantivity to substrates
containing hydroxyl groups or polar groups, e.g. wood, cellulose,
cotton or skin. The unique hydrophilic & hydrophobic nature of
these materials allows compatibility with a wide range of
molecules, including biomaterial such as enzymes.
The resultant films have many uses in personal and healthcare
applications, especially on the skin, where they can serve as, for
example, topical drug delivery systems, masking systems for skin
protection in dermal treatments, wound dressings and bandages for
minor wounds, burns, acute and chronic wounds, skin sealants, skin
protective films, scar treatments, exfoliation and hair remover
products, deodorizing films, antiperspirant active and fragrance
delivery systems, anti-wrinkle patches and moisturizing masks,
wherein said film applications have benefits in topical therapies,
wound care, surgical closure, scar care, underarm care, foot care,
body and face skin care, cosmetics, make-up and foundations. They
can likewise be used on other biological surfaces such as hair,
nails, teeth, eyes, and mucous membranes as well as similar
applications on animals other than humans and a variety of
applications on flora.
The present invention relates to using certain formulations for
forming films on substrates, preferably biological substrates,
where they can serve, for example, as barrier films, cosmetic
films, drug delivery mechanisms, wound management devices and the
like.
One embodiment of the invention provides a film forming
composition. The film-forming composition comprises a) a
saccharide-siloxane copolymer; b) a crosslinking agent; c) one or
more active/inactive ingredients; and d) optionally, a solvent, or
solvent mixture. The saccharide-siloxane copolymer has the
following formula:
R.sub.2aR.sub.1(3-a)SiO--[(SiR.sub.2R.sub.1O)m-(SiR.sub.12O)n]y--SiR.sub.-
1(3-a)R.sub.2a that is formulaically designated and also designated
according to specific embodiment needs. The saccharide-siloxane
copolymer is a reaction product of a functionalized organosiloxane
polymer and at least one hydroxy-functional saccharide such that
the organosiloxane component is covalently linked via a linking
group to the saccharide component.
The film-forming composition may be cured and then employed in the
manufacture of articles, or may be applied directly to a substrate
and cured in situ to form a cohesive and substantive film. The
composition provides the capability of controlled release of the
active or inactives in a variety of suitable cosmetics,
pharmaceutical and medical applications.
When applied and cured in situ, the substrate can be any kind of
biological tissue of vegetal, animal or human origin. For example,
in specific human applications, the substrate may be skin, scar,
corn, blister, wounded tissue, lip, nail, hair, eye-hair, mucosa,
or the like.
Other embodiments provide articles of manufacture including films,
bandages, topical and transdermal drug delivery patches, cosmetic
delivery vehicles and wound dressings comprising the novel
film-forming compositions.
These and other embodiments of the present invention will be more
fully understood by reference to the detailed description and
Examples set forth below.
The present invention provides novel film-forming compositions
comprising crosslinkable saccharide-siloxane copolymers wherein the
crosslinking substantially occurs between the hydroxy-functional
groups of the saccharide components, and cured films comprising the
crosslinked networks. The crosslinking occurring between the
hydroxyl functionalities of the saccharide backbone of the
copolymers is unique and forms a three-dimensional network having a
unique matrix. Consequently, the films formed therefrom possess
unique property profiles. The resulting films combine the
properties of siloxanes, for example, softness, vapor permeability,
hydrophobicity, good aesthetic feel, adhesive release, &
flexibility with the attributes of saccharides like substantivity
to substrates containing hydroxyl groups or polar groups, e.g.
wood, cellulose, cotton or skin. The unique hydrophilic &
hydrophobic nature of these materials allows compatibility with a
wide range of molecules, including biomaterial such as enzymes. The
cross-linked networks are particularly suitable for the entry and
controlled release of actives and inactives and the film-forming
compositions comprise active and/or inactive ingredients.
The film-forming compositions may be used as adhesive release films
on biological surfaces, for topical administration of medicaments
or other benefit-conferring actives, as protective barriers, or as
wound dressings, or for purposes of transdermal release of the
active or inactive ingredients. These films may also provide
film-forming attributes for personal care products for hair, skin
or antiperspirants. The crosslinkable composition in solvents may
provide gellant properties desirable for other applications.
Articles of manufacture comprising the novel film forming
compositions may be adapted for a variety of useful functions,
including but not limited to providing preservative, protective,
defensive, and/or reactive functions to textiles and clothing,
including those intended to be worn in the context of provision or
receipt of health care services or during military engagement.
One embodiment is directed to a film-forming composition. The
film-forming composition comprises: a) a saccharide-siloxane
copolymer; b) a crosslinking agent; c) one or more active/inactive
ingredients; and d) optionally, a solvent, or solvent mixture. The
saccharide-siloxane copolymer has the following formula:
R.sub.2aR.sub.1(3-a)SiO--[(SiR.sub.2R.sub.1O)m-(SiR.sub.12O)n]y-SiR.sub.1-
(3-a)R.sub.2a
wherein R.sub.1 can be the same or different and comprises
hydrogen, C1-C12 alkyl, an organic radical, or R.sub.3-Q,
Q comprises an epoxy, cycloepoxy, primary or secondary amino,
ethylenediamine, carboxy, halogen, vinyl, allyl, anhydride, or
mercapto functionality,
m and n are integers between 0 and 10,000 and may be the same or
different,
a is independently 0, 1, 2, or 3,
y is an integer such that the copolymer has a molecular weight less
than 1 million,
R.sub.1(3-a)SiO--[(SiR.sub.1O)m-(SiR.sub.12O)n]y--SiR.sub.1(3-a)
comprises an organosiloxane polymer component,
R.sub.2 has the formula Z-(G1)b-(G2)c, and there is at least one
R.sub.2,
wherein G1 is a saccharide component comprising 5 to 12
carbons,
b+c is 1-10, b or c can be 0, either b or c must be 1,
G2 is a saccharide component comprising 5 to 12 carbons
additionally substituted with organic or organosilicon
radicals,
Z is a linking group between the organosiloxane polymer component
and the saccharide component and is independently selected from the
group consisting of:
--R.sub.3--NHC(O)--R.sub.4--;
--R.sub.3--NHC(O)O--R.sub.4--;
--R.sub.3--NH--C(O)--NH--R.sub.4--;
--R.sub.3--C(O)--O--R.sub.4--;
--R.sub.3--O--R.sub.4--;
--R.sub.3--S--R.sub.4--;
--R.sub.3--CH(OH)--CH2-O--R.sub.4--;
--R.sub.3--CH(OH)--CH2-NH--R.sub.4--; and
--R.sub.3--N(R.sub.1)--R.sub.4, and
R.sub.3 and R.sub.4 are divalent spacer groups comprising
(R.sub.5)r(R.sub.6)s(R.sub.7)t,
where at least one of r, s and t must be 1, and
R.sub.5 and R.sub.7 are either C1-C12 alkyl or ((C1-C12)O)p where p
is any integer 1-50 and each (C1-C12)O may be the same or
different,
R.sub.6 is --N(R.sub.8)-, where R.sub.8 is H or C1-C12 alkyl.
The saccharide-siloxane copolymer is a reaction product of a
functionalized organosiloxane polymer and at least one
hydroxy-functional saccharide such that the organosiloxane
component is covalently linked via the linking group, Z, to the
saccharide component.
According to specific embodiments, the saccharide-siloxane
copolymer comprises a hydroxyl functionality of at least three and
the at least one polyhydroxyl-functional saccharide comprises an
aldonic acid or an oligoaldonic acid. In more specific embodiments
the aldonic acid or the oligoaldonic acid comprises a lactone, and
in very specific embodiments the lactone comprises a gluconolactone
or lactobionolactone. Examples of suitable linking groups include,
but are not limited to, an amide, an amino, a urethane, a urea, an
ester, an ether, a thioether, or an acetal linking group. According
to a preferred embodiment, the saccharide-siloxane is the reaction
product of a gluconolactone with an aminopropyl-terminated
polydimethylsiloxane whereby a polydimethylsiloxane having pendant
aminoethylaminoisobutyl groups is reacted with gluconolactone at
1:1 primary amine:lactone stoichiometry.
The crosslinking agent comprises any agent capable of crosslinking
a hydroxyl-functional polymer. The crosslinker may be selected from
the following non-limiting list: boric acid, borate ester (e.g.
tri-n-propyl borate, triisopropanolamine borate), alkyl boronic
acid or ester (e.g. phenyl boronic acid), titanate, (e.g. titanium
isopropoxide, diisopropoxytitanium bis(acetylacetonate)),
zirconate, glyoxal, gluteraldehyde, epichlorohydrin,
urea-formaldehyde, zirconium ammonium carbonate, salt of a
multivalent ion, bifunctional epoxy or glycidyl compounds (e.g. 1,4
butanediol diglycidyl ether), di-(N-hydroxymethyl)urea,
di-isocyanate (e.g. toluene diisocyante, hexamethylene
diisocyanate), 2-chloro N,N di-ethylacetamide, sodium
trimetaphosphate, phosphorous oxychloride, acrolein, N-methyl urea,
dicarboxylic acid, bis-acid chloride, dialkyldichlorosilane (e.g.
dimethyldichlorosilane), alkyltrichlorosilane (e.g.
Methyltrichlorosilane), reactive siloxane resin, and combinations
thereof.
According to another embodiment, the film-forming composition
further comprises one or more additional saccharide-siloxane
copolymers and suitable cross linkers to form a blended
film-forming composition. These blends may be designed to confer
more than one benefit according to the copolymers selected.
Once delivered onto a biological substrate, the film-forming
composition cures to form a cohesive and substantive film. The
present inventive compositions are easy to cure, and cure readily
with exposure to ambient conditions. Another embodiment of the
present invention is directed to a method for delivering at least
one active or inactive agent either topically to a biological
substrate, or transdermally through a biological substrate.
According to one specific embodiment, the film-forming composition
is applied wet to the biological substrate and the composition
cures in situ to form a film directed on the biological substrate.
In another specific embodiment, the film-forming composition is
first cured and then applied adhesively to the biological
substrate.
The one or more active or/and inactive ingredients contemplated for
inclusion in the film-forming compositions may be selected from the
following: a catalyst; a filler; a pigment; a UV stabilizer; a
fragrance; an essential oil; a thermal stabilizer; a rheology
modifier; a thickener; an adhesion promoter; a biocide; a
preservative; an enzyme; a peptide; a pressure sensitive adhesive;
a surface-active agent; a pharmaceutical active; a cosmetic
ingredient; a resin; and an aqueous ingredient. The substrate can
be any kind of biological tissue from vegetal, animal or human
origin. For example in human application, the substrate can be
skin, scar, corn, blister, wounded tissue, lip, nail, hair,
eye-hair, or mucosa.
According to specific embodiments, the biological substrate
comprises skin, and, more specifically, human skin. The film may be
useful for the treatment of cosmetic, medical or pharmaceutical
indications, and may be incorporated into such articles of
manufacture as wound dressings, bandages, topical or transdermal
drug delivery patches, cosmetic compositions, or fragrance delivery
patches. In particular embodiments, the wound dressing may comprise
a film-forming composition wherein the active agent comprises one
or more antibiotics, biocides or fungicides.
According to another embodiment, a transdermal drug delivery patch
is provided comprising the novel film-forming compositions. The
active is typically dispersed through out the cross-linked matrix
and the active or inactive ingredients diffuse passively from the
film or patch through the skin. The stratum corneum is the top most
layer of skin that serves as the greatest barrier to drug
diffusion. For certain desired agents, this natural barrier
significantly reduces or prevents passive diffusion. In these
instances enhancing devices, such as devices that create micropores
in the stratum corneum, including, for example, microstructured
arrays, sometimes called microneedles, that, when applied to the
skin, painlessly create micropores in the stratum corneum without
causing bleeding, may be suitably employed. These micropores offer
lower resistance to drug diffusion than normal skin without
micropores. Ablation of the stratum corneum from the epidermal
layer is also a well-known enhancement process and includes, for
example, ablation by laser systems. The inventive patch comprising
the film-forming composition may then be applied to the ablated
area to achieve transdermal delivery. Transdermal delivery via the
novel films and patches is particularly useful for delivery of
medicaments or pharmaceutical agents targeting systemically
treatable conditions.
Excipients may be added to the film-forming composition to improve
drug solubility and stability in the formulation and enhance the
permeation of the drug across the skin. Chemical permeation
enhancers are known in the art and are suitable excipients for
inclusion in the present inventive formulations.
Methods for making the film-forming compositions are also provided.
In one such embodiment the method comprises the steps of: a)
dissolving a saccharide-siloxane copolymer in a suitable solvent to
form a solution; b) dissolving at least one crosslinking agent in a
suitable solvent to form a solution; c) adding the solution from b)
into the solution from a) and mixing until b) is dispersed in a).
The saccharide-siloxane copolymer comprises a reaction product of a
functionalized organosiloxane polymer and at least one
polyhydroxy-functional saccharide such that the organosiloxane
polymer is covalently linked via a linking group to at least one
polyhydroxyl-functional saccharide. Active or nonactive ingredients
are preferably added to the composition prior to curing. Other
additives are optional and may be included at none, one, some or
all of steps a), b) and c), and are mixed until dispersed. Some
agents or additives may require pre-dissolution in a suitable
vehicle such as a solvent. The degree to which the additive
incorporates into the matrix, and the ionic character of the
additive influence the timeframe of addition. Additives may include
but are not limited to: d) a catalyst; e) a filler; f) a pigment;
g) a UV stabilizer; h) a thermal stabilizer; i) a rheology
modifier; j) a thickener; k) an adhesion promoter; I) a biocide; m)
a preservative; n) an enzyme; o) a peptide; p) a pressure sensitive
adhesive, or any surface active agent. r) a cosmetic active, s) an
antiperspirant compound, t) a UV screen agent, u) an active
pharmaceutical ingredient (API), v) an insecticide, w) an
anti-parasitic agent, or x) a fertilizer
Alternatively, the saccharide siloxane can be prepared in the
carrier solvent, eliminating the need to first isolate the
saccharide siloxane. A cutback method is necessary to incorporate
the silica because of the reduced sugar siloxane solution
viscosity. This is done by alternating small increment additions of
the silica filler and sugar siloxane solution to the formulation
followed by mixing.
Film embodiments include for example, topical drug delivery
systems, masking systems for skin protection in dermal treatments,
wound dressings and bandages for minor wounds, burns, acute and
chronic wounds, skin sealants, skin protective films, scar
treatments, exfoliation and hair remover products, deodorizing
films, antiperspirant active and fragrance delivery systems,
anti-wrinkle patches and moisturizing masks, wherein said film
applications have benefits in topical therapies, wound care,
surgical closure, scar care, underarm care, foot care, body and
face skin care, cosmetics, make-up and foundations. They can
likewise be used on other biological surfaces such as hair, nails,
teeth, eyes, and mucous membranes as well as similar applications
on animals other than humans and a variety of applications on
flora.
The present formulations can also comprise fillers. The fillers can
include, but are not limited to, ground, precipitated, and
colloidal calcium carbonates which can be untreated or treated with
stearate or stearic acid; reinforcing silicas such as fumed
silicas, precipitated silicas, and hydrophobed silicas; crushed
quartz, ground quartz, alumina, aluminum hydroxide, titanium
dioxide, diatomaceous earth, iron oxide, carbon black, and
graphite. One class of preferred fillers are synthetic silicas
where the surfaces of the silica are modified with silicon
compounds to produce a hydrophobic behavior. These materials differ
from one another in surface area, the silicon compound used to
treat the silica, and the extent of surface treatment. Such
materials are surprisingly able to reduce the viscosity of the film
forming formulation. In addition, resinous reinforcing fillers can
be used herein to form transparent films. Silica, calcium carbonate
and resinous fillers are especially preferred. Specific examples
include Cab-O-Sil.RTM. PTG, Cab-O-Sil.RTM. TS-530 treated filler,
Aerosil.RTM. R8200 treated filler, and Wacker HDX H2000 treated
filler.
If used, the amount of filler in the formulation is generally that
amount which provides the desired properties to the uncured
formulation such as viscosity, thixotropy, pigmentation, and UV
protection. The amount of filler also depends upon the cured
physical properties desired such as tensile strength, elongation,
and durometer. Finally, the amount of filler also depends on the
amounts of other components added, as well as the hydroxyl content
of the specific filler used. Typically, this is an amount in the
range of about 0.1 to 25 weight percent based on the total weight
of the formulation. Preferably, the filler is added in amounts from
about 2 to 15 weight percent on the same basis. The filler may be a
single filler or a mixture of two or more fillers.
The formulation can also comprise fluorinated fluids, resins,
organosiloxane polymers and resins. These materials provide
additional properties to the film including but not limited to:
softness, flexibility, higher adhesion to substrates like skin and
plastic films, pressure sensitive adhesive surface activity, lower
coefficient of friction, lubricity, or modified permeability.
Examples of fluorinated fluids are fluorinated siloxanes,
trifluoropropylmethyl siloxane. Examples of resins are rosin type
resins and acrylic polymer resins. Examples of organosiloxane
polymers are silicone polyethers, silicone polyamides, and silicone
acrylic copolymers. Examples of organosiloxane resins are siloxane
MQ resins.
Therapeutic active agents which may be employed according to the
present invention include, for example, anti-acne agents,
antibiotic, antiseptic, antifungal, antibacterial, antimicrobial,
biocides, anti-inflammatory, astringents, hormones, anticancer
agents, smoking cessation compositions, cardiovascular, histamine
blocker, bronchodilator, analgesic, anti-arrhythmic, antihistamine,
alpha-I blocker, beta blocker, ACE inhibitor, diuretic,
antiaggregant, sedative, tranquilizer, anticonvulsant,
anticoagulant agents, vitamins, antiaging agents, agents for
treating gastric and duodenal ulcers, anticellulites, proteolytic
enzymes, healing factors, cell growth nutrients, peptides and
others. Specific examples of suitable therapeutic active agents
include silver derivatives, penicillins, cephalosporins,
tetracyclines, macrolides, epinephrine, amphetamines, aspirin,
acetominophen, barbiturates, catecholamines, benzodiazepine,
thiopental, codeine, morphine, procaine, lidocaine, benzocaine,
sulphonamides, ticonazole, perbuterol, furosamide, prazosin,
prostaglandins, salbutamol, indomethicane, diclofenac, glafenine,
dipyridamole, theophylline and retinol.
In addition to the therapeutic or diagnostic materials, active
ingredients may be cosmetics such as perfumes, UV protectors,
shaving products, deodorants or the like. Suitable cosmetics are
known to those skilled in the art.
The proportion of the active agent employed in the present
invention is chosen in accordance with the concentration of the
active agent required in the composition to deliver the dosage
required at the proposed delivery rate. This may vary within a wide
range such as from 0.1 to about 70 weight percent, preferably 0.1
to 20 weight percent, of the final composition.
The film-forming compositions may also contain other additional
ingredients. One advantageous additive is a water scavenger to
prevent early curing of the formulation. Other optional ingredients
include colorants, colored indicators, other diluents, extenders
such as silicone fluids, silicone resins, excipients employed in
pharmacy, compounds intended to perform as pH buffers in
controlling the environment immediately in and around the
formulation, stabilizers, preservatives, surfactants for cellular
formulations such as fluorinated silicones, processing aids such as
cyclic or linear polydiorganosiloxanes, bioadhesive materials, and
hydrophilic, modulating and swellable components or polymers as set
forth in EP Publication 465,744. Still other additional ingredients
include absorbents for wounds, alginate, polysaccharides, gelatin,
collagen, and materials that can decrease the friction on the
surface of the cured film and/or change its gloss.
Some additional examples of the cosmetics, personal care, and
cosmeceutical ingredients and pharmaceutical excipients that may be
used herein may be found in the CTFA ingredient Database and the
handbook of pharmaceutical excipients and can include, for example,
essential oils, absorbents, anticacking agents, antioxidants,
antistatic agents, astringents, binders, buffering agents, bulking
agents, chelating agents, colorants, cosmetic astringents, cosmetic
biocides, deodorant agents, emollients, external analgesics, film
formers, flavoring agents, fragrance ingredients, humectants, lytic
agents, moisturizing agents, occlusivity enhancers, opacifying
agents, oxidizing and reducing agents, penetration enhancers,
pesticides, plasticizers, preservatives, skin bleaching agents,
skin conditioning agents, skin protectants, slip modifiers,
solubilizing agents, solvents, sunscreen agents, surface modifiers,
surfactants and emulsifying agents, suspending agents, thickening
agents, viscosity controlling agents including increasing or
decreasing agents, UV light absorbers,
Cosmetic, personal care and cosmeceutical ingredients, and
pharmaceutical excipients which may be employed are selected, for
example, from the following chemical classes: alcohols, fatty
alcohols and polyols, aldehydes, alkanolamines, alkoxylated
alcohols (e.g. polyethylene glygol derivatives of alcohols and
fatty alcohols), alkoxylated amides, alkoxylated amines,
alkoxylated carboxylic acids, amides including salts (e.g.
ceramides), amines, amino acids including salts and alkyl
substituted derivatives, esters, alkyl substituted and acyl
derivatives, polyacrylic acids, acrylamide copolymers, adipic acid
copolymers, alcohols, aminosilicones, biological polymers and
derivatives, butylene copolymers, carbohydrates (e.g.
polysaccharides, chitosan and derivatives), carboxylic acids,
carbomers, esters, ethers and polymeric ethers (e.g. PEG
derivatives, PPG derivatives), glyceryl esters and derivatives,
halogen compounds, heterocyclic compounds including salts,
hydrophilic colloids and derivatives including salts and gums (e.g.
cellulose derivatives, gelatin, xanthan gum, natural gums),
imidazolines, inorganic materials (clay, TiO2, ZnO), ketones (e.g.
camphor), isethionates, lanolin and derivatives, organic salts,
phenols including salts (e.g. parabens), phosphorus compounds (e.g.
phosphate derivatives), polyacrylates and acrylate copolymers,
protein and enzymes derivatives (e.g. collagen), synthetic polymers
including salts, siloxanes and silanes, sorbitan derivatives,
sterols, sulfonic acids and derivatives and waxes.
Examples of essential oils are Arnica (Arnica Montana), Basil
(Ocimum Basilicum), Bergamot (Citrus Bergamia), Cedarwood (Cedrus
Atlantica), Chamomile Roman (Chamaemelum Nobile), Cinnamon
(Cinnamomum Cassia), Cinnamon Bark (Cinnamomum Verum), Cistus
Labdanum (Cistus Ladanifer), Clary Sage (Salvia Sclarea), Clove
(Syzygium Aromaticum) Eugenol, Coriander (Coriandrum Sativum),
Cypress (Cupressus Sempervirens), Dill (Anethum Graveolens), Elemi
(Canarium Luzonicum), Eucalyptus Dives (Eucalyptus Dives),
Eucalyptus Globulus (Eucalyptus Globulus), Eucalyptus Polybractea
(Eucalyptus Polybractea), Eucalyptus Radiata (Eucalyptus Radiata),
Fennel (Foeniculum Vulgare), Fir Douglas (Pseudotsuga Menziesii),
Fir White (Abies Grandis), Frankincense (Boswellia Carteri),
Galbanum (Ferula Gummosa), Geranium (Pelargonium Graveolens),
Ginger (Zingiber Officinale), Goldenrod (Solidago Canadensis), Gotu
Kola (Centella Asiatica), Grapefruit (Citrus Paradisi), Helichrysum
(Helichrysum Italicum), Hyssop (Hyssopus Officinalis), Idaho Balsam
Fir (Abies Balsamea), Idaho Balsam Fir (Abies Balsamea), Jasmine
(Jasminum Officinale), Juniper (Juniperus Osteosperma, Juniperus
Scopulorum), Laurus Nobilis (Laurus Nobilis), Lavender (Lavandula
Angustifolia), Ledum (Ledum Groenlandicum), Lemon (Citrus Limon),
Lemongrass (Cymbopogon Flexuosus), Marjoram (Origanum Majorana),
Melaleuca Alternifolia Or Tea Tree Oil (Melaleuca Alternifolia),
Melaleuca Ericifolia (Melaleuca Ericifolia), Melissa (Melissa
Officinalis), Mountain Or Winter Savory (Satureja Montana), Myrrh
(Commiphora Myrrha), Myrtle (Myrtus Communis), Nutmeg (Myristica
Fragrans), Orange (Citrus Aurantium), Oregano (Origanum Compactum),
Palmarosa (Cynopogon Martinii), Patchouly (Pogostemon Cablin),
Pepper, Black (Piper Nigrum), Peppermint (Mentha Piperita), Petit
Grain (Citrus Aurantium), Pine (Pinus Sylvestris), Ravensara
(Ravensara Aromatica), Rose (Rosa Damascena), Rosemary (Rosmarinus
Officinalis), Rosewood (Aniba Rosaeodora), Sage (Salvia
Officinalis), Sandalwood (Santalum Album), Spearmint (Mentha
Spicata), Spikenard (Nardostachys Jatamansi), Spruce (Picea
Mariana), St John's Wort (Hypericum Perforatum), Tangerine (Citrus
Reticulata), Tansy Idaho (Tanacetum Vulgare), Tarragon (Artemisia
Dracunculus), Thyme (Thymus Vulgaris), Tsuga (Tsuga Canadensis),
Valerian (Valariana Officinalis), Vetiver (Vetiveria Zizanioides),
Western Red Cedar (Thuja Plicata), Wintergreen (Gaultheria
Procumbens), Ylang Ylang (Cananga Odorata).
Non-limiting examples of antiacne agents include salicylic acid,
benzoyl peroxide, vitamins, and sulfur, and non-limiting examples
of antifungal agents are calcium undecylenate, undecylenic acid,
zinc undecylenate, and povidone-iodine.
Examples of antimicrobial agents and biocides include, but are not
limited to, alcohols, benzalkonium chloride, benzethonium chloride,
hydrogen peroxide, methylbenzethonium chloride, phenol, poloxamer
188, povidone-iodine, polyhexamethylene biguanide hydrochloride,
silver derivatives including salt and nano silver, and xylitol.
Examples of antioxidants include, but are not limited to, acetyl
cysteine, arbutin, ascorbic acid, ascorbic acid polypeptide,
ascorbyl dipalmitate, ascorbyl methylsilanol pectinate, ascorbyl
palmitate, ascorbyl stearate, BHA, p-hydroxyanisole, BHT, t-butyl
hydroquinone, caffeic acid, camellia sinensis oil, chitosan
ascorbate, chitosan glycolate, chitosan salicylate, chlorogenic
acids, cysteine, cysteine HCl, decyl mercaptomethylimidazole,
erythorbic acid, d-limonene, diamylhydroquinone,
di-t-butylhydroquinone, dicetyl thiodipropionate,
dicyclopentadiene/t-butylcresol copolymer, digalloyl trioleate,
dilauryl thiodipropionate, dimyristyl thiodipropionate, dioleyl
tocopheryl methylsilanol, isoquercitrin, diosmine, disodium
ascorbyl sulfate, disodium rutinyl disulfate, distearyl
thiodipropionate, ditridecyl thiodipropionate, dodecyl gallate,
ethyl ferulate, ferulic acid, hydroquinone, hydroxylamine HCl,
hydroxylamine sulfate, Isooctyl thioglycolate, kojic acid,
madecassicoside, magnesium ascorbate, magnesium ascorbyl phosphate,
melatonin, methoxy-PEG-7 rutinyl succinate, methylene
di-t-butylcresol, methylsilanol ascorbate, nordihydroguaiaretic
acid, octyl gallate, phenylthioglycolic acid, phloroglucinol,
potassium ascorbyl tocopheryl phosphate, thiodiglycolamide,
potassium sulfite, propyl gallate, rosmarinic acid, rutin, sodium
ascorbate, sodium ascorbyl/cholesteryl phosphate, sodium bisulfite,
sodium erythorbate, sodium metabisulfide, sodium sulfite, sodium
thioglycolate, sorbityl furfural, tea tree (melaleuca altemifolia)
oil, tocopheryl acetate, tetrahexyldecyl ascorbate,
tetrahydrodiferuloylmethane, tocopheryl linoleate/oleate,
thiodiglycol, tocopheryl succinate, thiodiglycolic acid,
thioglycolic acid, thiolactic acid, thiosalicylic acid,
thiotaurine, retinol, tocophereth-5, tocophereth-10,
tocophereth-12, tocophereth-18, tocophereth-50, tocopherol,
tocophersolan, tocopheryl linoleate, tocopheryl nicotinate,
tocoquinone, o-tolyl biguanide, tris(nonylphenyl) phosphite,
ubiquinone, and zinc dibutyldithiocarbamate.
Examples of cosmetic biocides include, but are not limited to,
aluminum phenolsulfonate, ammonium phenolsulfonate, bakuchiol,
benzalkonium bromide, benzalkonium cetyl phosphate, benzalkonium
chloride, benzalkonium saccharinate, benzethonium chloride,
potassium phenoxide, benzoxiquine, benzoxonium chloride,
bispyrithione, boric acid, bromochlorophene, camphor benzalkonium
methosulfate, captan, cetalkonium chloride, cetearalkonium bromide,
cetethyldimonium bromide, cetrimonium bromide, cetrimonium
chloride, cetrimonium methosulfate, cetrimonium saccharinate,
cetrimonium tosylate, cetylpyridinium chloride, chloramine T,
chlorhexidine, chlorhexidine diacetate, chlorhexidine digluconate,
chlorhexidine dihydrochloride, p-chloro-m-cresol, chlorophene,
p-chlorophenol, chlorothymol, chloroxylenol, chlorphenesin,
ciclopirox olamine, climbazole, cloflucarban, clotrimazole, coal
tar, colloidal sulfur, o-cymen-5-ol, dequalinium acetate,
dequalinium chloride, dibromopropamidine diisethionate,
dichlorobenzyl alcohol, dichlorophene, dichlorophenyl
imidazoldioxolan, dichloro-m-xylenol, diiodomethyltolylsulfone,
dimethylol ethylene thiourea, diphenylmethyl
piperazinylbenzimidazole, domiphen bromide,
7-ethylbicyclooxazolidine, fluorosalan, formaldehyde, glutaral,
hexachlorophene, hexamidine, hexamidine diisethionate, hexamidine
diparaben, hexamidine paraben, hexetidine, hydrogen peroxide,
hydroxymethyl dioxoazabicyclooctane, ichthammol, isopropyl cresol,
lapyrium chloride, lauralkonium bromide, lauralkonium chloride,
laurtrimonium bromide, laurtrimonium chloride, laurtrimonium
trichlorophenoxide, lauryl isoquinolinium bromide, lauryl
isoquinolinium saccharinate, laurylpyridinium chloride, mercuric
oxide, methenamine, methenammonium chloride, methylbenzethonium
chloride, myristalkonium chloride, myristalkonium saccharinate,
myrtrimonium bromide, nonoxynol-9 iodine, nonoxynol-12 iodine,
olealkonium chloride, oxyquinoline, oxyquinoline benzoate,
oxyquinoline sulfate, PEG-2 coco-benzonium chloride, PEG-10
coco-benzonium chloride, PEG-6 undecylenate, PEG-8 undecylenate,
phenol, o-phenylphenol, phenyl salicylate, piroctone olamine,
sulfosuccinylundecylenate, potassium o-phenylphenate, potassium
salicylate, potassium troclosene, propionic acid, PVP-iodine,
quaternium-8, quaternium-14, quaternium-24, sodium phenolsulfonate,
sodium phenoxide, sodium o-phenylphenate, sodium shale oil
sulfonate, sodium usnate, thiabendazole,
2,2'-thiobis(4-chlorophenol), thiram, triacetin, triclocarban,
triclosan, trioctyldodecyl borate, undecylenamidopropylamine oxide,
undecyleneth-6, undecylenic acid, zinc acetate, zinc aspartate,
zinc borate, zinc chloride, zinc citrate, zinc cysteinate, zinc
dibutyldithiocarbamate, zinc gluconate, zinc glutamate, zinc
lactate, zinc phenolsulfonate, zinc pyrithione, zinc sulfate, and
zinc undecylenate.
External analgesics are also suitable ingredients and include, for
example, benzyl alcohol, capsicum oleoresin (capsicum frutescens
oleoresin), methyl salicylate, camphor, phenol, capsaicin, juniper
tar (juniperus oxycedrus tar), phenolate sodium (sodium phenoxide),
capsicum (capsicum frutescens), menthol, resorcinol, methyl
nicotinate, and turpentine oil (turpentine). Oxidizing agents
suitably employable include, for example, ammonium persulfate,
calcium peroxide, hydrogen peroxide, magnesium peroxide, melamine
peroxide, potassium bromate, potassium caroate, potassium chlorate,
potassium persulfate, sodium bromate, sodium carbonate peroxide,
sodium chlorate, sodium iodate, sodium perborate, sodium
persulfate, strontium dioxide, strontium peroxide, urea peroxide,
and zinc peroxide, while reducing agents suitably employable
include, for example, ammonium bisufite, ammonium sulfite, ammonium
thioglycolate, ammonium thiolactate, cystemaine hcl, cystein,
cysteine HCl, ethanolamine thioglycolate, glutathione, glyceryl
thioglycolate, glyceryl thioproprionate, hydroquinone,
p-hydroxyanisole, isooctyl thioglycolate, magnesium thioglycolate,
mercaptopropionic acid, potassium metabisulfite, potassium sulfite,
potassium thioglycolate, sodium bisulfite, sodium hydrosulfite,
sodium hydroxymethane sulfonate, sodium metabisulfite, sodium
sulfite, sodium thioglycolate, strontium thioglycolate, superoxide
dismutase, thioglycerin, thioglycolic acid, thiolactic acid,
thiosalicylic acid, and zinc formaldehyde sulfoxylate.
A non-limiting example of a suitable skin bleaching active agent is
hydroquinone, and examples of skin protectants include, but are not
limited to, allantoin, aluminum acetate, aluminum hydroxide,
aluminum sulfate, calamine, cocoa butter, cod liver oil, colloidal
oatmeal, dimethicone, glycerin, kaolin, lanolin, mineral oil,
petrolatum, shark liver oil, sodium bicarbonate, talc, witch hazel,
zinc acetate, zinc carbonate, and zinc oxide.
Nonlimiting examples of sunscreen agents include aminobenzoic acid,
cinoxate, diethanolamine methoxycinnamate, digalloyl trioleate,
dioxybenzone, ethyl 4-[bis(hydroxypropyl)]aminobenzoate, glyceryl
aminobenzoate, homosalate, lawsone with dihydroxyacetone, menthyl
anthranilate, octocrylene, octyl methoxycinnamate, octyl
salicylate, oxybenzone, padimate O, phenylbenzimidazole sulfonic
acid, red petrolatum, sulisobenzone, titanium dioxide, and
trolamine salicylate, and examples specifically of UV light
absorbing agents include acetaminosalol, allatoin PABA,
benzalphthalide, benzophenone, benzophenone 1-12, 3-benzylidene
camphor, benzylidenecamphor hydrolyzed collagen sulfonamide,
benzylidene camphor sulfonic acid, benzyl salicylate, bornelone,
bumetriozole, butyl methoxydibenzoylmethane, butyl PABA,
ceria/silica, ceria/silica talc, cinoxate, dea-methoxycinnamate,
dibenzoxazol naphthalene, di-t-butyl hydroxybenzylidene camphor,
digalloyl trioleate, diisopropyl methyl cinnamate, dimethyl PABA
ethyl cetearyldimonium tosylate, dioctyl butamido triazone,
diphenyl carbomethoxy acetoxy naphthopyran, disodium bisethylphenyl
tiamminotriazine stilbenedisulfonate, disodium d istyrylbiphenyl
triaminotriazine stilbened isulfonate, disodium distyrylbiphenyl
disulfonate, drometrizole, drometrizole trisiloxane, ethyl
dihydroxypropyl PABA, ethyl diisopropylcinnamate, ethyl
methoxycinnamate, ethyl PABA, ethyl urocanate, etrocrylene ferulic
acid, glyceryl octanoate dimethoxycinnamate, glyceryl PABA, glycol
salicylate, homosalate, isoamyl p-methoxycinnamate, isopropylbenzyl
salicylate, isopropyl dibenzolylmethane, isopropyl
methoxycinnamate, menthyl anthranilate, menthyl salicylate,
4-methylbenzylidene, camphor, octocrylene, octrizole, octyl
dimethyl PABA, octyl methoxycinnamate, octyl salicylate, octyl
triazone, PABA, PEG-25 PABA, pentyl dimethyl PABA,
phenylbenzimidazole sulfonic acid, polyacrylamidomethyl benzylidene
camphor, potassium methoxycinnamate, potassium phenylbenzimidazole
sulfonate, red petrolatum, sodium phenylbenzimidazole sulfonate,
sodium urocanate, tea-phenylbenzimidazole sulfonate,
tea-salicylate, terepbthalylidene dicamphor sulfonic acid, titanium
dioxide, triPABA panthenol, urocanic acid, and
va/crotonates/methacryloxybenzophenone-1 copolymer.
Since the formulation cures at room temperature after evaporation
of the solvent, the component materials can be mixed and stored in
a evaporation proof container. It can be stored in a plurality of
containers prior to use to inhibit curing or inhibition when
co-formulated with excipients and actives prior to use. Suitable
containers include, for example, single use containers (e.g., foil
packets, tubes, soft capsules, blisters, wipes) or multiple use
containers (e.g. roll-on, tube with foam pad, pen like system,
pumps and sprays, brush-in-bottle). It is often desirable to put a
diluent in both containers.
According to particular methods of the invention, the curable
formulation is applied to the desired site or, alternatively, the
component materials of the invention can be applied onto the
desired site in a manner that causes mixing. The formulation reacts
when the solvent evaporates and results in a cured composition.
Preferably, the formulations are applied on a biological surface
including, but not limited to animal bodies (e.g., human or other
animal) and flora.
The formulations of the invention can be applied, for example, by
rubbing, painting, spraying, wiping, or any other conventional
method of applying thin films.
As noted above, when the formulation is applied, it dries and cures
rapidly at room temperature in the presence of moisture (e.g.,
within 10 minutes, usually within 1-2 minutes). For example, the
formulation will cure rapidly on a human or other animal body. If
used on an animal, this can minimize the amount time necessary to
keep the area immobile while curing takes place.
The final composition can be in the form of a gel or an elastomer
and it can have pores (e.g., foams) or it can be pore-free. If the
final composition has pores, the formulations might contain
materials such as blowing agents to form the pores.
The present invention offers numerous advantages over the prior
art. The method described herein allows for a simple method of
forming a film on a substrate. As such, a skilled practitioner is
not required for application. Moreover, the composition can be
formed into a wide variety of shapes and have selected combinations
of properties (e.g. bioadhesion, release rate and release profile).
Similarly, the formulations and processes described herein don't
involve severe conditions (e.g. high temperatures or pressures)
that might damage any active agents or substrates used.
The formulations and resultant compositions herein are generally
acceptable on many biological surfaces. The composition may be
formed on intact or damaged skin or in a natural or artificial
cavity of the body. The cavity may be, for example, the ocular,
buccal, nasal, aural, vaginal or rectal cavity or a cavity formed,
for example, in a tooth or an open wound.
The resultant films are typically thin and non-tacky. Films on the
order of up to 500 microns (e.g., 2.5 microns to 250 microns) are
often obtained. These films can have many physical properties from
gels to elastomers so that they are able to withstand many of the
pressures exerted during normal activities of a patient.
The invention allows for a film former that can be applied to skin,
intact or damaged, in order to form a protective barrier or deliver
an active (cosmetic or pharmaceutical). The success criteria are
film forming property, non stinging if applied to damaged skin,
substantivity (e.g. long lasting wear time), resistance to water,
removability, adjustable permeability, permeability to actives,
ability to be co-formulated, and stability.
The following examples are set forth to illustrate certain
embodiments of the invention, and should not be construed as
limiting the scope of the invention as defined by the claims.
Unless indicated, all parts are by weight and all viscosities are
at 25.degree. C.
Example 1
This Example illustrates formulation of saccharide-siloxane
composition XX-5501. Certain formulation embodiments of the present
invention are made by blending, for example, the components listed
in the silicone and organic excipient lists below, with the
saccharide-siloxane composition designated herein as XX-5501 and
prepared as per the protocol set forth below.
The polymer GL-8211 used to prepare the saccharide-siloxane
composition XX-5501 is the reaction product of a gluconolactone
with an aminopropyl-terminated polydimethylsiloxane according to
the following procedure: DC.RTM. 2-8211 Polymer (Dow Corning Corp.,
Midland, Mich.), a 1000 cst. polydimethylsiloxane with pendant
aminoethylaminoisobutyl groups (approximately 1.9 mole percent), is
reacted with gluconolactone at 1:1 primary amine:lactone
stoichiometry in methanol at 50.degree. C. Upon completion of the
reaction, the methanol is removed with rotary evaporation. The
resulting material has a gum-like consistency.
The saccharide siloxane composition XX-5501 is prepared according
to the following procedure: 45 g of GL-8211 saccharide-siloxane as
prepared above, is diluted with a 90/10 by weight solution of 0.65
cSt 200 Fluid (Dow Corning Corp, Midland Mich.) and 200 proof
ethanol until a 50% copolymer concentration is achieved. The
dilution is accomplished by sequential additions of the solvent
followed by mixing on a Hauschild Speedmixer.TM. centrifugal mixer
(Flacktek, Inc. Landrum, S.C.) until homogenous. The crosslinker is
a 10% by weight solution of phenyl boronic acid (Sigma-Aldrich Co.,
St. Louis, Mo.) in 200 proof ethanol. Cab-o-sil TS-530 is a
hexamethyldisilazane treated silica (Cabot Co. Boston, Mass.). The
saccharide-siloxane solution, treated silica, and crosslinker
solutions are mixed on a Hauschild Speedmixer.TM. centrifugal mixer
(Flacktek, Inc. Landrum, S.C.) until homogenous.
Batches of XX-5501 were prepared with different levels of
cross-linker:
19786-93 contained 0.7 percent of cross-linker phenyl boronic acid.
41.6 wt. % solid content. 19809-129A contained 0.5 percent of
cross-linker phenyl boronic acid. 44 wt. % solid content.
19809-129B contained 2.0 percents of cross-linker phenyl boronic
acid. 42 wt. % solid content. Exemplary Active and Inactive
Ingredients a. Silicone Excipients (Available from Dow Corning
Corporation) Dow Corning.RTM. 193 fluid--INCI name: PEG-12
dimethicone Dow Corning.RTM. 2503 cosmetic wax--INCI name: Stearyl
dimethicone-CAS # 67762-83-8 Dow Corning FA 4001 CM Silicone
Acrylate--INCl name: cyclopentasiloxane and
Acrylates/Polymethylsiloxymethacrylate copolymer Dow Corning FA
4002 ID Silicone Acrylate--INCI name: Isododecane and
Acrylates/Polymethylsiloxymethacrylate copolymer b. Organic
Excipients Arnica Montana tincture--Composition: Alcohol and water
and Amica montana flower extracted, Supplier: Dolisos Centella
Asiatica dry extract--INCI name: Centella asiatica dry extract, CAS
# 84696-21-8, Supplier: Linnea Hypericum Perforatum dry
extract--FNC.TM. name: Hypericum perforatum flower/leaf/stem
extract, CAS # 84082-80-4, Supplier: Linnea Calcium Alginate--INCI
name: Calcium alginate, CAS # 9002-35-0, Supplier: Sigma-Aldrich
Reach 103--INCI name: Aluminum chlorohydrate, CAS # 1327-41-9,
Supplier: Reheis Essential oil of Aniba Rosaedora--INCI name: Aniba
rosaedora (rosewood) wood oil, CAS # 8015-77-8, Supplier: Plaisir
d'essence Essential oil of Cinnamomum Cassia--INCI name: Cinnamomum
Cassia leaf oil, CAS # 8007-77-8, Supplier: Plaisir d'essence
Essential oil of Eucalyptus Radiata--INCI name: Eucalyptus radiate,
CAS # n.a., Supplier: Plaisir d'essence Essential oil of Eucalyptus
Citriodora--INCI name: Eucalyptus Citriodora oil, CAS # 8000-48-4,
Supplier: Plaisir d'essence Essential oil of Eucalyptus
Globulus--CAS # 8000-48-4, Supplier: Plaisir d'essence Essential
oil of Eucalyptus Dives ssp Piperitoniferum--CAS # n.a., Supplier:
Plaisir d'essence Essential oil of Eucalyptus Smithii--CAS # n.a.,
Supplier: Plaisir d'essence Essential oil of Mentha Piperita--CAS #
8006-90-4, Supplier: Plaisir d'essence Essential oil of Cinopogon
Martini--CAS #8014-19-5, Supplier: Plaisir d'essence
Lidocaine--Formule: C14H22N2O, CAS #137-58-6, Supplier:
Sigma-Aldrich Ethyl 4-Aminobenzoate PH Eur--Technical name:
benzocaine, CAS #94-09-7, Supplier: Sigma-Aldrich NaCl/Sodium
Chloride--INCI name: sodium chloride, CAS #7647-14-5, Supplier:
Sigma-aldrich Castor oil--INCI name: Ricinus communis (CAStor) seed
oil, CAS # 8001-79-4, Supplier: Sigma-Aldrich Absolute
ethanol--INCI name: Alcohol, CAS # 64-17-5, Supplier:
Fisher-bioblock Propylene glycol--INCI name: Propylene glycol, CAS
# 57-55-6, Supplier: Sigma-Aldrich Glycerin--INCI name: Glycerin,
CAS # 56-81-5, Supplier: Sigma-Aldrich
Example 2
This Example illustrates a formulation of the film-forming
cross-linkable saccharide-siloxane and one or more active/inactive
ingredients according to certain embodiments of the present
invention.
Preparation Procedure:
a. The saccharide-siloxane solution and the active or inactive
ingredient are weighed and mixed on a Hauschild Speedmixer.TM.
centrifugal mixer (Flacktek, Inc. Landrum, S.C.) for 20 s at 2000
rpm. b. film of wet saccharide siloxane containing the active or
inactive ingredient is coated on fluorinated liner using lab
coating table and 100 .mu.m shims. Testing Procedure: a. The drying
time is measured with a chronometer. The film is considered dry
when it doesn't stick to the finger. b. Film appearance--The film
is observed visually for shine, transparency through the film,
transparency on a paper (could we read a text through the film when
the film is on a book), general appearance smooth or rough. c.
Mechanical properties--A rectangle of 2 cm.times.5 cm is cut in
each film and evaluated for cohesion by stretching the film between
fingers.
TABLE-US-00001 TABLE 1 XX-5501 #19786-93 Ingredient Drying Time
Ingredient (wt. %) (wt. %) (seconds) Cohesion Stickiness Appearance
XX-5501 100 0 25-30 Good Dry Transparent Propylene glycol 98.6 2.4
30 Low Sticky Propylene glycol 88 12 35 Low Sticky Propylene glycol
76 24 Wet Low Wet PG droplets Arnica Montana 98.6 2.4 24 Good Dry
White tincture Arnica Montana 88 12 35 Good Dry White, opaque
tincture Arnica Montana 76 24 47 Good Dry White, opaque tincture
NaCl 98.6 2.4 30 Good Dry Visible salt grain NaCl 88 12 30 Good Dry
Visible salt grain NaCl 76 24 28 Good Dry Aluminum 98.6 2.4 33 Good
Dry White chlorohydrate Aluminum 88 12 28 Good Dry Small grain
chlorohydrate Aluminum 76 24 29 Good Dry Small grain chlorohydrate
Cinnamomum 88 12 22 Good Dry Yellow Cassia Cinnamomum 76 24 27 Good
Dry Yellow Cassia Ethanol 76 24 Good Dry Like XX001 Lidocaine 88 12
32 Fair Dry Opaque Lidocaine 76 12 Fair Dry Opaque Cinopogon
Martini 76 24 Good Slow drying Aniba Rosaedora 76 24 Good Slow
drying Eucalyptus Radiata 76 24 Good Dry Yellow Mentha Piperita 76
24 Good Slow drying
Example 3
This Example illustrates the formulation of XX-5501 batch
19809-129, A and B with one or more actives/inactives according to
certain embodiments of the present invention.
Preparation Procedure:
a. The saccharide-siloxane solution and the active or inactive
ingredient are weighed and mixed on a Hauschild Speedmixer.TM.
centrifugal mixer (Flacktek, Inc. Landrum, S.C.) for 20 s at 2000
rpm. b. A film of wet saccharide-siloxane containing the ingredient
is coated on fluorinated liner using lab coating table and 100
.mu.m shims. Testing Procedure: a. The dying time is measured with
a chronometer. The film is considered dry when it doesn't stick to
the finger.
TABLE-US-00002 TABLE 2 XX-5501 XX-5501 #19809-129A #19809-129B
Ingredient Drying Time Drying Time Ingredient (wt. %) (seconds)
(seconds) NO 0 20-30 20-30 Arnica montana tincture 1 25 31 Centella
Asiatica 1% of 45 >30 (dispersed in PG) Centella Propylene
glycol 10 90 34 Propylene glycol 1 35 33 Hypericum Perforatum 1% of
40 138 (dispersed in PG) Hypericum Calcium alginate 1 28 27
Aluminum chlorohydrate 1 31 30 Aniba Rosaedora 1 27 29 Cinnamomum
Cassia 1 32 37 Eucalyptus Radiata 1 22 21 Mentha piperita 1 32 33
Cynopogon Martini 1 29 48 Lidocaine (dispersed in 1% of 34 38
ethanol) lidocaine Benzocaine (dispersed in 1% of 44 37 ethanol)
benzocaine Ethanol 2 52 43 Ethanol 4 48 51 NaCl 1 25 31 Castor oil
1 130 42 Castor oil 2 130 47
Example 4
Preparation Procedure:
a. The saccharide-siloxane solution and the active or inactive
ingredient are weighed and mixed on a Hauschild Speedmixer.TM.
centrifugal mixer (Flacktek, Inc. Landrum, S.C.) for 20 s at 2000
rpm. b. A film of wet saccharide-siloxane containing the ingredient
is coated on fluorinated liner using lab coating table and 100
.mu.m shims. Testing Procedure: a. Film appearance, the film is
observed visually for shine, transparency through the film,
transparency on a paper (readability through the film), global
appearance (smooth or rough).
TABLE-US-00003 TABLE 3 Ingredient wt. % Transparency Ability to
read in XX-5501 through the a text though Ingredient #19809-129A
Shine Smoothness film the film Comment XX-5501 #19809- 0 High High
Medium High 129A Arnica montana 1 High High Medium High tincture
Centella Asiatica 1% of Centella High High Medium High (dispersed
in PG) Propylene glycol 10 High High Medium High Propylene glycol 1
High High Medium Medium Hypericum 1% of High High High High yellow
Perforatum Hypericum (dispersed in PG) Calcium alginate 1 High Low
Medium Medium Grain Aluminum 1 Low Low Low Low chlorohydrate Aniba
Rosaedora 1 High High Medium Medium Fragrance release Cinnamomum 1
Low High Medium Low Yellow Cassia Fragrance release Eucalyptus
Radiata 1 Low Low Low Low Yellow Fragrance release Mentha piperita
1 Low Medium Medium High Fragrance release Cynopogon 1 Medium High
Medium High Fragrance Martini release Lidocaine 1% of lidocaine
Medium High Medium High (dispersed in ethanol) Benzocaine 1% of
High High Medium Medium (dispersed in benzocaine ethanol) Ethanol 2
Medium High Medium Medium Ethanol 4 High High Medium Medium NaCl 1
Medium Low Medium Medium Grain Castor oil 1 Low Medium Medium
Medium Castor oil 2 Low Medium Medium medium
Example 5
Preparation Procedure:
a. The saccharide-siloxane solution and the active or inactive
ingredient are weighed and mixed on a Hauschild Speedmixer.TM.
centrifugal mixer (Flacktek, Inc. Landrum, S.C.) for 20 s at 2000
rpm. b. A film of wet saccharide-siloxane containing the ingredient
is coated on fluorinated liner using lab coating table and 100
.mu.m shims. Testing Procedure: a. mechanical properties--A
rectangle of 2 cm.times.5 cm is cut in each film and evaluated for
cohesion by stretching the film between fingers.
TABLE-US-00004 TABLE 4 Ingredient wt. % in XX- Removability from
Elastic Resistance to Ingredient 5501 #19809-129A fluorinated film
Modulus break Elongation XX-5501 #19809-129A 0 High High Medium Low
Arnica montana tincture 1 High High Medium Low Centella Asiatica 1%
of Centella High Medium Medium High (dispersed in PG) Propylene
glycol 10 High Medium Low High Propylene glycol 1 High Low Low Low
Hypericum Perforatum 1% of Hypericum Medium Medium Low High
(dispersed in PG) Calcium alginate 1 High Medium Medium Low
Aluminum chlorohydrate 1 Medium Medium Medium Low Aniba Rosaedora 1
High High High Low Cinnamomum Cassia 1 High High High Low
Eucalyptus Radiata 1 High High High Low Mentha piperita 1 High
Medium Medium Low Cynopogon Martini 1 High High Medium Low
Lidocaine (dispersed in 1% of lidocaine High Medium High Low
ethanol) Benzocaine (dispersed in 1% of benzocaine Medium Medium
Medium Medium ethanol) Ethanol 2 High Medium Medium Low Ethanol 4
Medium Low Medium Low NaCl 1 High Medium Medium Low Castor oil 1
High Medium Medium Medium Castor oil 2 Medium Medium Low High
Example 6
Preparation Procedure:
a. The saccharide-siloxane solution and the active or inactive
ingredient are weighed and mixed on a Hauschild Speedmixer.TM.
centrifugal mixer (Flacktek, Inc. Landrum, S.C.) for 20 s at 2000
rpm. b. A film of wet saccharide-siloxane containing the ingredient
is coated on fluorinated liner using lab coating table and 100
.mu.m shims. Testing Procedure: a. Film appearance, the film is
observed visually for shine, transparency through the film,
transparency on a paper (readability of a through the film), global
appearance smooth or rough.
TABLE-US-00005 TABLE 5 Ingredient wt. % Transparency Ability to
read in XX-5501 through the a text though Ingredient #19809-129B
Shine Smoothness film the film Comment XX-5501 #19809- 0 Medium
High Medium High 129B Arnica Montana 1 High High High High tincture
Centella Asiatica 1% of Centella High High High High (dispersed in
PG) Propylene glycol 10 Medium Medium High High Tacky Propylene
glycol 1 High High High High Hypericum 1% of Medium Low High High
Yellow Perforatum Hypericum Fragrance (dispersed in PG) release
Calcium alginate 1 Low Low Medium Medium Grain Aluminum 1 Low Low
Low Medium chlorohydrate Aniba Rosaedora 1 Medium High Medium
Medium Fragrance release Cinnamomum 1 Medium Medium Medium Medium
Fragrance Cassia release Eucalyptus Radiata 1 Low Low Low Medium
Fragrance release Mentha piperita 1 High High High Medium Fragrance
release Cynopogon 1 Medium High Medium Medium Fragrance Martini
release Lidocaine 1% of lidocaine Low High High High (dispersed in
ethanol) Benzocaine 1% of High High High Medium (dispersed in
benzocaine ethanol) Ethanol 2 Low High Low High Ethanol 4 Low High
Low Medium NaCl 1 Low Low High High Grain Castor oil 1 Medium High
High High Castor oil 2 Low Medium Medium medium
Example 7
Preparation Procedure:
a. The saccharide-siloxane solution and the active or inactive
ingredient are weighed and mixed on a Hauschild Speedmixer.TM.
centrifugal mixer (Flacktek, Inc. Landrum, S.C.) for 20 s at 2000
rpm. b. A film of wet saccharide-siloxane containing the ingredient
is coated on fluorinated liner using lab coating table and 100
.mu.m shims. Testing Procedure: a. mechanical properties--A
rectangle of 2 cm.times.5 cm is cut in each film and evaluated for
cohesion by stretching the film between fingers.
TABLE-US-00006 TABLE 6 ingredient wt. % in XX- Removability from
Elastic Resistance to Ingredient 5501 #19809-129B fluorinated film
Modulus break Elongation XX-5501 #19809-129B 0 Medium Medium Low
Low Arnica montana tincture 1 Medium High High Low Centella
Asiatica 1% of Centella Low Low Low Low (dispersed in PG) Propylene
glycol 10 Low Low Low Low Propylene glycol 1 Low Medium Low High
Hypericum Perforatum 1% of Hypericum Medium Medium Low High
(dispersed in PG) Calcium alginate 1 High High High Low Aluminum
chlorohydrate 1 High Medium Medium Low Aniba Rosaedora 1 High
Medium Medium Low Cinnamomum Cassia 1 High High High Low Eucalyptus
Radiata 1 High High High Low Mentha piperita 1 High High High Low
Cynopogon Martini 1 Medium Medium Medium Low Lidocaine (dispersed
in 1% of lidocaine Low Low Low Medium ethanol) Benzocaine
(dispersed in 1% of benzocaine Low Medium Medium High ethanol)
Ethanol 2 Medium Medium Low Medium Ethanol 4 Low Medium Low Low
NaCl 1 High Low Low Medium Castor oil 1 Medium Medium Medium Low
Castor oil 2 Medium Medium Medium Low
Example 8
Preparation Procedure:
a. The saccharide-siloxane solution and the active or inactive
ingredient are weighed and mixed on a Hauschild Speedmixer.TM.
centrifugal mixer (Flacktek, Inc. Landrum, S.C.) for 20 s at 2000
rpm. b. Preparation procedure: a film of wet saccharide-siloxane
containing the ingredient is coated on fluorinated liner using lab
coating table and 100 .mu.m shims. Testing Procedure: a. Film
appearance--The film is observed visually for shine, transparency
through the film, transparency on a paper (could we read a text
through the film when the film is on a book), general appearance
smooth or rough.
TABLE-US-00007 TABLE 7 Ingredient wt. % in XX-5501 Transparency
through Ability to read a text Ingredient #19809-129A Shine
Smoothness the film though the film XX-5501 #19809- 0 High High
Medium High 129A FA 4002 ID 1 Medium Medium Medium Medium FA 4002
ID 10 Low Medium Low Medium FA 4001 CM 1 Medium Medium High High FA
4001 CM 10 Low Low Medium High 193 Fluid 1 Medium Low Low Low 193
Fluid 5 Low Low Medium Medium Glycerin 1 Low Low Low Medium
Glycerin 5 Low Low Low Medium
Example 9
Preparation Procedure:
a. The saccharide-siloxane solution and the active or inactive
ingredient are weighed and mixed on a Hauschild Speedmixer.TM.
centrifugal mixer (Flacktek, Inc. Landrum, S.C.) for 20 s at 2000
rpm. b. Preparation procedure: a film of wet saccharide-siloxane
containing the ingredient is coated on fluorinated liner using lab
coating table and 100 .mu.m shims. Testing Procedure: a. Film
appearance--The film is observed visually for shine, transparency
through the film, transparency on a paper (could we read a text
through the film when the film is on a book), general appearance
smooth or rough.
TABLE-US-00008 TABLE 8 Ingredient wt. % in XX-5501 Transparency
through Ability to read a text Ingredient #19809-129B Shine
Smoothness the film though the film XX-5501 #19809- 0 High High
Medium High 129B FA 4002 ID 1 Medium Medium Medium Medium FA 4002
ID 10 Low Medium Medium Medium FA 4001 CM 1 Medium Low Low High FA
4001 CM 10 Low Low Low Medium 193 Fluid 1 High Low Medium Medium
193 Fluid 5 Low Medium Low Medium Glycerin 1 Medium Medium Low
Medium Glycerin 5 Low High Low Low
Example 10
Preparation Procedure:
a. The saccharide-siloxane solution and the active or inactive
ingredient are weighed and mixed on a Hauschild Speedmixer.TM.
centrifugal mixer (Flacktek, Inc. Landrum, S.C.) for 20 s at 2000
rpm. b. Preparation procedure: a film of wet saccharide-siloxane
containing the ingredient is coated on fluorinated liner using lab
coating table and 100 .mu.m shims. Testing Procedure: a. actives
were released in a good solvent (water) after 8 hours of digestion
at 32.degree. C. (skin temperature) in pressurized bombs (Parr
digestion system). After extraction, aqueous solutions were
analyzed by WDXKF in order to quantify the amounts of active
released from wound care films.
TABLE-US-00009 TABLE 9 NaCl AlCl3 Samples % extracted % extracted
XX-5501 #19786-93 0 0 XX-5501 #19786-93 + 2.4% NaCl 0 -- XX-5501
#19786-93 + 12% NaCl 2 -- XX-5501 #19786-93 + 24% NaCl 4 -- XX-5501
#19786-93 + 2.4% AlCl.sub.3 -- 50 XX-5501 #19786-93 + 12%
AlCl.sub.3 -- 14 XX-5501 #19786-93 + 24% AlCl.sub.3 -- 10
Example 11
This example illustrates the effect of Cab-O-Sil treated and
untreated silicas in the formulation, on viscosity.
The saccharide siloxane composition XX-5501 is prepared according
to the following procedure: 52.5 g of GL-8211 saccharide-siloxane
as prepared in Example 1 is diluted with a 90/10 by weight solution
of 0.65 cSt 200 Fluid (Dow Corning Corp, Midland Mich.) and 200
proof ethanol until a 50% copolymer concentration is achieved. The
dilution is accomplished by sequential additions of the solvent
followed by mixing on a Hauschild Speedmixer.TM. centrifugal mixer
(Flacktek, Inc. Landrum, S.C.) until homogenous. The crosslinker is
a 10% by weight solution of phenyl boronic acid (Sigma-Aldrich Co.,
St. Louis, Mo.) in 200 proof ethanol. 3.94 g of this crosslinker
solution and 4.73 g silica is added to the formulation. The
saccharide-siloxane solution, silica, and crosslinker solutions are
mixed on a Hauschild Speedmixer.TM. centrifugal mixer (Flacktek,
Inc. Landrum, S.C.) until homogenous. At the end 90/10
hexamethyldisiloxane/ethanol solvent mixture is added to achieve
35% solid saccharide-siloxane concentration in the final
formulation.
Cab-O-Sil TS-530 is a hexamethyldisilazane treated silica and
Cab-O-Sil PTG is an untreated fumed silica (Cabot Co. Boston,
Mass.).
Table 10 summarizes the viscosity measurements of the formulations
prepared with treated and untreated Cab-O-Sil.RTM. silicas over 3
months testing period.
TABLE-US-00010 TABLE 10 crosslinker Viscosity Viscosity Viscosity
Viscosity level after prep. 1 month 2 month 3 month Silica Type
(pts) (cps) (cps) (cps) (cps) Cab-O-Sil 1.5 1,200 2,200 25,600
70,000 TS-530 Cab-O-Sil 1.5 2,720 1,900 1,600 1,360 PTG
The data demonstrates that the viscosity of the untreated silica
formulation is slightly decreased, while the viscosity of the
treated silica formulation is increased largely over the testing
period.
The samples were evaluated on surface, also. The friction and dirt
resistance of the untreated silica containing films were
enhanced.
Example 12
This example illustrates the effect on the physical characteristics
of the film from varying the crosslinker concentration. Samples are
prepared as in Example 11, above, except that the crosslinker
concentration is altered between 0.1-2.0 pts calculated to the
siloxane content.
Film samples were drawn from the formulations having various
crosslinker concentrations. The appearance of the film samples at
and under 1.5 pts were smooth without any bubbles, which were
observed at higher crosslinker concentrations.
The physical characteristic data set forth in Table 11 demonstrates
the dependence of the tensile strength and elongation of the sugar
siloxane film formers on the crosslinker concentration.
TABLE-US-00011 TABLE 11 Crosslinker Tensile 50% 100% Concentration
Strength Elongation Toughness Modulus Modulus (pts) (psi) (%)
(lbf/in.sup.2) (psi) (psi) 0.1 80.5 99.3* 68.7 81.4 85.4 0.5 85.2
187.5 155.2 82.9 99.4 1.0 99.5 161.6 155.2 100.2 115.9 1.5 151.7
132.0 168.2 140.5 163.2 2.0 174.8 59.5 69.2 187.8 --
The tensile strength of the 1.5 pts crosslinker film was slightly
less, but the elongation value was improved compared to the
benchmark formulation. The physical properties of the saccharide
siloxane films with lower than 1.5 pts crosslinker concentrations
were undesirable.
Example 13
This Example illustrates in-solvent saccharide-siloxane
synthesis.
The saccharide siloxane polymer is prepared in 90/10 (w/w)
hexamethyldisiloxane (0.65 cSt 200 Fluid, Dow Corning Corp.,
Midland, Mich.)/200 proof ethanol solvent system according to the
following procedure: DC.RTM. 2-8211 Polymer is reacted with
gluconolactone (1:1 lactone to amine functional group
stoichiometry) in MM/EtOH solvent system at 70.degree. C. for 6
hours. GC analysis is used to detect ethanol and
hexamethyldisiloxane content in final product.
A "cutback method" is necessary to incorporate the Cab-O-Sil PTG
untreated silica (Cabot Co., Boston, Mass.), because of the reduced
saccharide siloxane solution viscosity. The cutback method involves
alternating small incremental additions of the silica filler and
saccharide siloxane solution to the formulation followed by mixing
on a Hauschild Speedmixer.TM. centrifugal mixer (Flacktek, Inc.
Landrum, S.C.) until homogeneous formulation achieved. Finally, a
10% solution in ethanol of the phenylboronic acid crosslinker is
added and mixed.
Example 14
The data set forth in Table 12 details the properties of two
exemplary polymers that were reacted with the saccharide and tested
in the film forming formulation. DC.RTM. 2-8211 has nominally a
functional group per every 53 dimethylsiloxy units compared to
DC.RTM. 2-8460, which has one functional group per 42
dimethylsiloxy units.
TABLE-US-00012 TABLE 12 Polymer Name MW DP mpc F 2-8211 22932 300
1.9 Q2-8460 31445 410 2.4
The DC.RTM. 2-8211-GL and DC.RTM. Q2-8460 saccharide siloxane
polymers are prepared in 90/10 (w/w) hexamethyldisiloxane (0.65 cSt
200 Fluid, Dow Corning Corp., Midland, Mich.)/200 proof ethanol
solvent system according to the following procedure: The amino
siloxane polymer is reacted with gluconolactone (1:1 lactone to
amine functional group stoichiometry) in MM/EtOH solvent system at
70.degree. C. for 6 hours. GC analysis is used to detect ethanol
and hexamethyldisiloxane content in final product.
A cutback method is necessary to incorporate the Cab-O-Sil PTG
untreated silica (Cabot Co., Boston, Mass.), because of the reduced
saccharide siloxane solution viscosity. This is done by alternating
small incremental additions of the silica filler and saccharide
siloxane solution to the formulation followed by mixing on a
Hauschild Speedmixer.TM. centrifugal mixer (Flacktek, Inc. Landrum,
S.C.) until homogeneous formulation achieved. Finally, a 10%
solution in ethanol of the phenylboronic acid crosslinker is added
and mixed. 66.34 g of polymer solution in 90/10 (w/w)
hexamethyldisiloxane/200 proof ethanol solvent system, 4.73 g of
untreated silica and 3.94 g of crosslinker solution are used in
each formulation.
Films were drawn from each formulation and physical properties were
compared to each other as set forth in Table 13.
TABLE-US-00013 TABLE 13 Tensile Silicone Polymer Strength
Elongation Type (psi) at break % DC .RTM. 8211-GL 118.9 61.68 DC
.RTM. Q2-8460-GL 234.9 77.93
Notably, the film prepared with the DC.RTM. 8460-GL is stronger
than the 8211-GL containing matrix. The increased strength may be
due to the greater number of reactive sites per polymer in the
DC.RTM. 2-8460.
Example 15
This Example illustrates drug incorporation and drug release from
films according to specific embodiments of the invention and
provides two examples of drug-incorporated formulations suitable
for drug delivery applications.
The saccharide siloxane polymer is prepared in 90/10 (w/w)
hexamethyldisiloxane (0.65 cSt 200 Fluid, Dow Corning Corp.,
Midland, Mich.)/200 proof ethanol solvent system according to the
following procedure: DC.RTM. 2-8211 Polymer is reacted with
gluconolactone (1:1 lactone to amine functional group
stoichiometry) in MM/EtOH solvent system at 70.degree. C. for 6
hours. GC analysis is used to detect ethanol and
hexamethyldisiloxane content in final product. Once again, a
cutback method, as described above, is necessary to incorporate the
Cab-O-Sil PTG untreated silica. Finally, a 10% solution in ethanol
of the phenylboronic acid crosslinker is added and mixed. 17.69 g
of polymer solution in 90/10 (w/w) hexamethyldisiloxane/200 proof
ethanol solvent system, 0.2 g of an exemplary drug agent, 1.06 g of
untreated silica and 1.05 g of crosslinker solution are used in
each formulation. Two active drugs, Niacinamide and Ketoconazole,
respectively, were incorporated into drug delivery films employing
this protocol. Determination of active agent release was conducted
using Franz static diffusion cells having defined receiving
volumes. Data are set forth graphically in FIGS. 1A and B.
* * * * *